U.S. patent number 4,723,039 [Application Number 06/937,716] was granted by the patent office on 1988-02-02 for phenylacetaldehydes substituted by basic groups, their preparation and drugs containing these compounds.
This patent grant is currently assigned to BASF Aktiengesellschaft. Invention is credited to Verena Baldinger, Josef Gries, Dieter Lenke, Manfred Raschack, Klaus Ruebsamen, Werner Seitz.
United States Patent |
4,723,039 |
Seitz , et al. |
February 2, 1988 |
Phenylacetaldehydes substituted by basic groups, their preparation
and drugs containing these compounds
Abstract
Phenylacetaldehydes which are substituted by basic groups, of
the formula ##STR1## where R.sup.1 to R.sup.8, m and n have the
meanings stated in the description, and their preparation are
described. The substances are useful for the treatment of
disorders.
Inventors: |
Seitz; Werner (Plankstadt,
DE), Baldinger; Verena (Heidelberg, DE),
Gries; Josef (Wachenheim, DE), Lenke; Dieter
(Ludwigshafen, DE), Raschack; Manfred (Weisenheim am
Sand, DE), Ruebsamen; Klaus (Neustadt,
DE) |
Assignee: |
BASF Aktiengesellschaft
(Ludwigshafen, DE)
|
Family
ID: |
6287695 |
Appl.
No.: |
06/937,716 |
Filed: |
December 4, 1986 |
Foreign Application Priority Data
Current U.S.
Class: |
564/344; 564/304;
564/342; 568/424; 514/926; 564/316; 564/345; 600/481; 600/485 |
Current CPC
Class: |
C07D
317/58 (20130101); A61P 9/00 (20180101); C07D
319/18 (20130101); A61P 1/04 (20180101); A61P
9/12 (20180101); Y10S 514/926 (20130101) |
Current International
Class: |
C07D
317/00 (20060101); C07D 319/18 (20060101); C07D
317/58 (20060101); C07D 319/00 (20060101); C07C
095/08 () |
Field of
Search: |
;568/424,433
;564/344,342,345 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
64158 |
|
Mar 1985 |
|
EP |
|
747866 |
|
Apr 1952 |
|
GB |
|
Other References
Arzneim-Forsch/Drug Res., 31 (I), No. 5 (1981), pp. 773-780. .
Drugs of Today, vol. 20, No. 2 (1984), pp. 69-90..
|
Primary Examiner: Lone; Werren B.
Attorney, Agent or Firm: Keil & Weinkauf
Claims
We claim:
1. A phenylacetaldehyde substituted by basic groups, of the formula
I ##STR6## where R.sup.1, R.sup.2, R.sup.3, R.sup.6, R.sup.7 and
R.sup.8 are identical or different and are each hydrogen, halogen,
trifluoromethyl, C.sub.1 -C.sub.4 -alkyl, nitro or C.sub.1 -C.sub.4
-alkoxy, and two radicals in adjacent positions may furthermore
together form methylenedioxy, ethylenedioxy,
1,3-dioxatetramethylene, propylene or butylene, R.sub.4 is a
saturated or unsaturated C.sub.1 -C.sub.12 -alkyl group, a
cycloalkyl group or an aryl group, R.sup.5 is C.sub.1 -C.sub.4
-alkyl and m and n are identical or different and are each 2, 3 or
4, and its salts with physiologically tolerated acids.
2. (RS)-2-[3-[(Phenylethyl)-methylamino]-propyl]
-2-isopropylphenylacetaldehyde and its enantiomers.
3. (RS)-2-[3-[(3-Methoxyphenylethyl)-methylamino]pr
opyl]-2-isopropyl-3,4-dimethoxyp henylacetaldehyde and its
enantiomers.
4.
(RS)-2-[3-[(3-Methoxyphenylethyl)-methylamino]propyl]-2-isopropyl-3,
4,5-trimethoxyphenylacetaldehyde and its enantiomers.
5. (RS)-2-[3-[(3,5-Dimethoxyphenylethyl)-methylamino]
1-propyl]-2-isopropyl-3,5-dimethoxyphenylacetaldehyde and its
enantiomers.
6.
(RS)-2-[3-[(3-Ethoxyphenylethyl)-methylamino]propyl]-2-isopropyl-3-ethox
yphenylacetaldehyde and its enantiomers.
7. (RS)-2-[3-[(3,5-Diethoxyphenylethyl)-
methylamino]propyl]-2-isopropyl-3,5-diethoxyphenylacetaldehyde and
its enantiomers.
8. A method of treating circulatory disorders including cardiac
diseases, high blood pressure, and disturbances of blood flow which
comprises administering to a patient suffering from such a disorder
an effective amount of a compound of the formula I as described in
claim 1 or its salts with physiologically tolerated acid.
9. A method of treating gastric and duodenal ulcers which comprises
administering to a patient suffering from said ulcers an effective
amount of a compound of the formula I as described in claim 1 or
its salts with physiologically tolerated acids.
Description
The present invention relates to novel phenylacetaldehydes
substituted by basic groups, their preparation and drugs which
contain these substances.
German Patent No. 1,154,810 and European Laid-Open Application No.
64,158 describe phenylacetonitriles which are substituted by basic
groups. From this class of compounds, verapamil and gallopamil have
proven useful in the therapy of coronary heart diseases and of high
blood pressure. Relationships between the chemical structure and
biological action of the verapamil molecule have been described in
various publications (cf. Arzneim. Forsch./Drug Res. 5 (1981),
773). On the basis of these structure/action considerations and
experimental work, Mannhold [Drugs of Today 20 (2) (1984), 69-90]
has shown that the nitrile group of the verapamil molecule is
essential for the biological action.
We have found compounds which are highly effective in spite of the
fact that the nitrile group has been converted.
The present invention relates to novel phenylacetaldehydes which
are substituted by basic groups and are of the formula I ##STR2##
where R.sup.1, R.sup.2, R.sup.3, R.sup.6, R.sup.7 and R.sup.8 are
identical or different and are each hydrogen, halogen,
trifluoromethyl, C.sub.1 -C.sub.4 -alkyl, nitro or C.sub.1 -C.sub.4
-alkoxy, and two radicals in adjacent positions may furthermore
together form methylene dioxy, ethylenedioxy,
1,3-dioxatetramethylene, propylene or butylene, R.sub.4 is a
saturated or unsaturated C.sub.1 -C.sub.12 -alkyl group, a
cycloalkyl group or an aryl group, R.sup.5 is C.sub.1 -C.sub.4
-alkyl and m and n are identical or different and are each 2, 3 or
4, and their salts with physiologically tolerated acids.
Preferred halogen atoms R.sup.1 to R.sup.3 and R.sup.6 to R.sup.8
are fluorine and chlorine. Preferred alkyl and alkoxy groups
R.sup.1 to R.sup.3 and R.sup.5 to R.sup.8 are those of 1 or 2
carbon atoms. Preferred nitro compounds are those which contain one
nitro group.
The following compounds are of particular interest:
(RS)-2-[3-[(phenylethyl)-methylamino]-propyl]-2-isopropylphenylacetaldehyde
(R)-2-[3-[(phenylethyl)-methylamino]-propyl]-2-isopropylphenylacetaldehyde,
(S)-2-[3-[(phenylethyl)-methylamino]-propyl]-2-isopropylphenylacetaldehyde,
(RS)-2-[3-[(3-methoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4-dime
thoxyphenylacetaldehyde,
(R)-2-[3-[(3-methoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4-dimet
hoxyphenylacetaldehyde,
(S)-2-[3-[(3-methoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4-dimet
hoxyphenylacetaldehyde,
(RS)-2-[3-[(3-methoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4,5-tr
imethoxyphenylacetaldehyde,
(R)-2-[3-[(3-methoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4,5-tri
methoxyphenylacetaldehyde,
(S)-2-[3-[(3-methoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4,5-tri
methoxyphenylacetaldehyde,
(RS)-2-[3-[(3,5-dimethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-
dimethoxyphenylacetaldehyde,
(R)-2-[3-[(3,5-dimethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-d
imethoxyphenylacetaldehyde,
(S)-2-[3-[(3,5-dimethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-d
imethoxyphenylacetaldehyde,
(RS)-2-[3-[(3-ethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3-ethoxyp
henylacetaldehyde,
(R)-2-[3-[(3-ethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3-ethoxyph
enylacetaldehyde,
(S)-2-[3-[(3-ethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-
3-ethoxyphenylacetaldehyde,
(RS)-2-[3-[(3,5-diethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-d
iethoxyphenylacetaldehyde,
(R)-2-[3-[(3,5-diethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-di
ethoxyphenylacetaldehyde,
(S)-2-[3-[(3,5-diethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-di
ethoxyphenylacetaldehyde.
Examples of suitable physiologically tolerated acids are
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, acetic acid, maleic acid, lactic acid, tartaric acid, citric
acid and fumaric acid.
The novel compounds possess one or more asymmetric carbon atoms and
are therefore obtained in the various enantiomeric forms.
Consequently, the compounds I can be prepared either in optically
active forms or as racemic mixtures. The racemates of the compounds
I can be resolved into their optical antipodes by conventional
techniques, for example by separation (fractional crystallization,
column chromatography) of the diastereomeric salts. These salts can
be prepared by reacting a compound I with a chiral acid. The
enantiomeric forms can also be obtained by using optically active
starting compounds.
The novel compounds are prepared by a process in which
(a) a phenylacetonitile of the formula II ##STR3## where R.sup.1 to
R.sup.8, m and n are as defined above, is reacted with a complex
aluminum hydride and the product is then hydrolyzed, or
(b) a phenylacetaldehyde of the formula III ##STR4## where R.sup.1
to R.sup.4 and m have the above meanings and Z is a leaving group,
is reacted with a phenylalkylamine of the formula IV ##STR5## where
R.sup.5 to R.sup.8 and n have the above meanings, and, if desired,
the resulting compound is converted to a salt with a
physiologically tolerated acid.
Complex aluminum hydrides which are suitable for reaction (a)
include the following: lithium aluminum hydride, sodium
bis-(2-methoxyethoxy)-aluminum dihydride, lithium and sodium
triethoxyaluminum hydride and preferably diisobutylaluminum
hydride.
The reaction is preferably carried out in an aprotic solvent, such
as toluene or hexane, or in an aliphatic or cyclic ether, such as
diethyl ether or tetrahydrofuran. The reaction temperature can be
chosen to be from -60.degree. C. to +20.degree. C., but the
reaction is preferably carried out at from -20.degree. to 0.degree.
C.
Reaction (b) is preferably carried out in a dipolar aprotic
solvent, e.g. acetonitile, dimethylformamide or
hexamethylphosphorotriamide, with the addition of an acid acceptor,
e.g. anhydrous potassium carbonate. An additional equivalent of the
phenylalkylamine of the formula IV may also be used as the acid
acceptor. The reaction temperature can be chosen to be from room
temperature to 120.degree. C., but the reaction is preferably
carried out at from 70.degree. to 100.degree. C.
Examples of suitable leaving groups are chlorine, bromine, iodine,
sulfuric ester groups, mesylates and triflates.
Phenylacetaldehydes of the formula III can be obtained by reduction
of the corresponding phenylacetonitriles with a complex aluminum
hydride.
The compounds of the general formula I and their physiologically
tolerated addition salts with acids have useful pharmacological
properties. They are highly active Ca antagonists and have a
dilatory effect on peripheral and central vessels, as well as
protecting the heart and vessels from damage caused by increased Ca
mobilization or Ca overloading. The compounds inhibit the secretion
of gastric acid and have a cytoprotective and antiulcerous effect.
Finally, they are capable of preventing or alleviating spasms of
the bronchial muscles.
This is shown by the following experiments:
Inhibition of secretion of gastric acid
Inhibition of the secretion of gastric acid is evident from an
increase in the pH of the surface of the gastric mucous membrane.
For this measurement, groups of from 5 to 10 female Sprague-Dawley
rats weighing 160-190 g, which had remained without food for 48
hours (water ad libitum), were pretreated with different doses of
the test substances, administered orally. 1 hour later, a pH probe
(Ingold 440 M.sub.3) was inserted into the stomach under inhalation
anesthesia with halothane, and the pH at the surface of the mucous
membrane was measured (pH for untreated animals: 1.40.+-.0.02,
N=200). The dose which produces an increase in the pH by 0.75 pH
units is determined as the ED 0.75, from the linear regression of
log dose and the increase in the pH.
Cytoprotective action
The cytoprotective action was determined on groups of 8 female
Sprague-Dawley rats weighing 160-190 g, the rats having received no
food for 48 hours (water ad libitum) and having been pretreated
with different doses of the test substances, administered orally. 1
hour later, 10 ml/kg of 100% ethanol were administered orally to
the animals. After a further hour, the animals were sacrificed by
inhalation of CO.sub.2, the stomach was removed and the intensity
of the lesions was assessed on the basis of the following
scheme:
0=unchanged mucous membrane
1=a few areas of reddening which are narrow, elongated or small
2=reddening over broad, elongated or large interrupted areas
3=pronounced reddening which colors virtually the entire mucous
membrane of the glandular stomach.
The dose which reduces lesions by 50% is determined as the ED 50%
from the linear regression of log dose and the reduction in the
intensity of the lesions of the gastric mucous membrane.
Antiulcerous action
To investigate the antiulcerous action, groups of 10 female
Sprague-Dawley rats weighing 160-180 g received 1 mg/kg of
reserpine, administered intraperitoneally, and thereafter remained
without food for 18 hours (water ad libitum). After this time, the
animals received 21.5 mg/kg of indomethacin, administered
intraperitoneally, and the test substance administered orally.
Thereafter, they were kept for 6 hours at 8.degree. C. and then
sacrificed. The stomach was removed and the area of the ulcerous
lesions on the mucous membrane was determined. The dose which
reduces the ulcerous area by 50% was determined as the ED 50%, from
the linear regressions of the logarithms of the doses adminsitered
and the relative reduction in the area of ulceration, based on the
control animals.
TABLE ______________________________________ Gastric acid
secretion-inhibiting, cytoprotective and antiulcerous effects in
the rat, oral administration Acid secretion- Cytoprotective
Antiulcerous Example inhibiting effect effect No. effect ED 0.75
(1) ED 50% ED 50% ______________________________________ Verapamil
10.5 (2) (2) 3 2.1 8.3 3.8 2 2.0 9.4 12.2
______________________________________ (1) Doses in mg/kg (2) No
effect
As demonstrated in Examples 3 and 2, the novel compounds inhibit
secretion of gastric acid in doses which are one-fifth of than that
required in the case of the comparative substance verapamil.
Moreover, they protect the gastric mucous membrane from the harmful
effect of ethanol and prevent the formation of gastric ulcers.
The cytoprotective and antiulcerous actions are two additional
effects, which are not shown by verapamil.
Hypotensive and antihypertensive action
To determine the hypotensive action, Sprague-Dawley rats weighing
230-280 g were anesthetized with urethane (1.78 g/kg, administered
intraperitoneally). The blood pressure was measured in the carotid
artery. The substances were administered intravenously into the
jugular vein. The dose which produces a 20% decrease in blood
pressure was calculated as the ED 20%, from the linear regression
of log dose (mg/kg) and relative decrease in blood pressure
(.DELTA.%).
To determine the antihypertensive action, the substances were
administered orally to spontaneously hypertensive male Okamoto rats
(4-8 animals/dose, weight 270-360 g). The systolic blood pressure
was measured noninvasively on the rat's tail with the aid of
piezoelectric transducers, before and 2 hours after administration.
The dose which reduces the systolic pressure by 20%, relative to
the values for untreated control animals, was determined as the ED
20%.
TABLE ______________________________________ Hypotensive action
Reduction in Reduction in blood pressure blood pressure rat,
anethetized, SH rat ED 20% i.v. ED 20% p.o. Example No. mg/kg R.A.
mg/kg R.A. ______________________________________ Verapamil 0.34
1.0 25 1.00 12 0.30 1.13 4.0 6.25
______________________________________
As shown in the table, when administered intravenously to the
anesthetized rat, the substance of Example 12 reduces the blood
pressure to a somewhat greater extent than verapamil.
It proves particularly effective when administered orally to
conscious spontaneously hypertensive rats. In this model, the
substance of Example 12 reduces the blood pressure when
administered in a dose which is 6.3 times smaller compared with
verapamil.
Broncholytic action
To test the broncholytic action, guinea pigs weighing from 300 to
450 g were anesthetized with urethane (1.5 g/kg, administered
intraperitoneally) and, after preparation, with pentobarbital (25
mg/kg, administered intravenously), and cannulae were inserted into
the trachea and the jugular vein.
The animals were artificially ventilated using a Starling pump.
Bronchospasms were induced by injecting histamine (from 0.001 to
0.00464 mg/kg) or acetylcholine (from 0.02 to 0.04 mg/kg) 2-3 times
at intervals of 10 minutes.
These bronchospasms were determined via inductive pressure
transducers, using the method due to Konsett and Rossler
(1940).
The substances, which were injected intravenously 5 minutes before
the bronchospasms were induced, inhibited these bronchospasms in a
dose-dependent manner.
For comparison, the dose which produces a 75% reduction in the
bronchospasms was determined as the ED 75%, from the linear
regressions of log dose and inhibition of spasms.
TABLE ______________________________________ Broncholytic action in
the guinea pig, intravenous adminis- tration ED 75%, mg/kg Example
Histamine-induced Acetylcholine-induced No. bronchospasm
bronchospasm ______________________________________ Verapamil 1.3
0.56 8 0.38 0.23 6 0.59 0.39 7 0.61 0.67 12 0.65 0.27
______________________________________
The table shows the broncholytic activity of the novel substances
and demonstrates that the substances of Examples 8, 6, 7 and 12
have a substantially higher activity compared with the reference
substance verapamil.
Calcium-antagonistic action in spiral strips of aorta
The Ca-antagonistic action was tested on spiral strips of aorta of
male and female Sprague-Dawley rats weighing from 200 to 300 g.
The animals were sacrificed with ether, and the thorax and thoracic
aorta were removed. A maximum of 6 spiral strips about 2 mm wide
and 2 cm long were used per animal.
The strips of aorta were suspended in a modified tyrode solution at
37.degree. C. and subjected to an initial tension with a load of
1.5 g and, after a relaxation time of about 1 hour, Ca was removed
by keeping them for 5 minutes in Ca-free tyrode solution with the
addition of 0.2 mM of Na EDTA.
The Ca-free strips of vessel were depolarized with K-rich tyrode
solution for 10 minutes. Contraction was induced by a CaCl.sub.2
concentration of 0.5 mM. After 15 minutes, Ca was again removed
from the strips of vessel by means of a Ca-free tyrode solution
containing 0.2 mM of Na EDTA.
Depolarization was then effected again for 10 minutes with K-rich
tyrode solution, after which 0.05 ml of the test substance was
added. After the test substance had been allowed to act for 15
minutes, CaCl.sub.2 was again added in a concentration of 0.5 mM in
order to check whether the test substance has a Ca-antagonistic
action. Inhibition of the effect of 0.5 mM Ca.sup.++ by the
antagonistic substance is stated as a percentage. The concentration
which produces 50% inhibition of the Ca effect is determined as the
EC 50% (on not less than 12 strips of vessel).
TABLE ______________________________________ Ca--antagonistic
action in isolated spiral strips of aorta of the rat (administered
in vitro) Example No. EC 50%, mol/l
______________________________________ Verapamil 3.5 .times.
10.sup.-8 7 2.2 .times. 10.sup.-8 12 3.2 .times. 10.sup.-8 11 1.2
.times. 10.sup.-8 10 1.9 .times. 10.sup.-8 9 1.2 .times. 10.sup.-9
______________________________________
The table shows the Ca-antagonistic of the novel substances and
indicates that the substances of Examples 11, 10 and 9 have a
substantially higher activity compared with the reference substance
verapamil.
Because of these effects, they can be used, for example, for the
prophylaxis and treatment of coronary heart disease, as
antihypertensive agents for the treatment of high blood pressure,
for peripheral and central disturbances of blood flow and for
cerebral oxygen deficiency.
They can also be employed for gastric disorders accompanied by
hypersecretion, for the treatment of gastric and duodenal ulcers
and as broncholytics for bronchospastic conditions.
The novel compounds can be administered orally or parenterally in a
conventional manner. The dose depends on the age, condition and
weight of the patient and on the route of administration. As a
rule, the daily dose of active compound is from about 0.1 to 10
mg/kg of body weight in the case of oral administration and from
0.01 to 1.0 mg/kg of body weight in the case of parenteral
administration. Normally, the daily dose is from 1 to 5 mg/kg for
oral administration and from 0.05 to 0.25 mg/kg for parenteral
administration.
The novel active compounds can be brought into the conventional
pharmaceutical forms, such as tablets, coated tablets, solutions,
emulsions, powders, capsules or depot forms, and the conventional
pharmaceutical auxiliaries and the conventional production methods
may be employed for their preparation. Appropriate tablets can be
obtained, for example, by mixing the active compounds with
conventional auxiliaries, for example inert diluents, such as
calcium carbonate, calcium phosphate or lactose, disintegrating
agents, such as corn starch or alginic acid, binders, such as
starch or gelatine, lubricants, such as magnesium stearate or talc,
and/or agents for achieving a depot effect, such as
carboxypolymethylene, carboxymethylcellulose, cellulose acetate
phthalate or polyvinyl acetate.
The tablets may furthermore consist of a plurality of layers.
Correspondingly, coated tablets can be prepared by coating cores,
prepared similarly to the tablets, with agents conventionally used
in tablet coatings, for example collidone or shellac, gum arabic,
talc, titanium dioxide or sugar. To achieve a depot effect or to
avoid incompatibility, the core may also consist of a plurality of
layers. The tablet shell too may consist of a plurality of layers
in order to achieve a depot effect, and the auxiliaries stated
above in connection with tablets may be used.
Syrups of the novel active compounds or combinations of active
compounds may additionally contain a sweetener, such as saccharin,
cyclamate, glycerol or sugar, and a flavor improver, for example
flavorings, such as vanillin or orange extract.
They may furthermore contain suspending agents or thickeners, such
as sodium carboxymethylcellulose, wetting agents, for example
condensates of fatty alcohols with ethylene oxide, or
preservatives, such as p-hydroxybenzoates.
Injectable solutions are prepared in a conventional manner, for
examples with the addition of preservatives, such as
p-hydroxybenzoates, or stabilizers, such as Komplexones, and are
introduced into injection bottles or ampoules.
Capsules containing the active compounds or combinations of active
compounds can be prepared, for example, by mixing the active
ingredients with inert carriers, such as lactose or sorbitol, and
encapsulating the mixture in gelatine capsules.
Suitable suppositories can be prepared, for example, by mixing the
envisaged active compounds as combinations of active compounds with
conventional carriers, such as neutral fats or polyethylene glycol
or its derivatives.
The novel compounds are also suitable for combining with other
pharmacodynamically effective substances, such as diuretics or
platelet aggregation inhibitors.
The Examples which follow illustrate the invention without
restricting it.
EXAMPLE 1
2-[3-[(Phenylethyl)methylamino]-propyl]-2-isopropylphenylacetaldehyde
180 ml of a 1M solution of diisobutylaluminum hydride in hexane
were added dropwise, at -5.degree. C., to a solution of 33.4 g (0.1
mole) of
2-[3-[(phenylethyl)-methylamino]-propyl]-isopropylphenylacetonitrile
in 400 ml of diethyl ether. The mixture was stirred for 1.5 hours,
after which 500 ml of 10% strength sulfuric acid were added. 30 g
of tartaric acid were introduced, the mixture was rendered alkaline
with concentrated potassium hydroxide solution, and the ether phase
was separated off and washed several times with sodium chloride
solution. After the ether phase had been dried over sodium sulfate,
the ether was distilled off, the remaining oily residue was
dissolved in 300 ml of ethyl acetate, and hydrochloric acid in
isopropanol was added. The mixture was left to stand overnight,
after which the precipitated hydrochloride was filtered off under
suction.
Yield: 31.5 g (85%) of hydrochloride
Mp. 166.degree.-168.degree. C.
The following were obtained in a similar manner:
EXAMPLE 2
(S)-2-[3-[(Phenylethyl)-methylamino]-propyl]-2-isopropylphenylacetaldehyde
hydrochloride, mp. 182.degree.-184.degree. C.
[.alpha.].sub.589.sup.20 =-7.2.degree. (c=20.1 mg/ml, ethanol, d=10
cm)
Analysis: calculated: C 73.9, H 8.6, Cl 9.5, N 3.8. found: C 73.8,
H 8.6, Cl 9.5, N 3.8.
EXAMPLE 3
(R)-2-[3-[(Phenylethyl)-methylamino]-propyl]-2-isopropylphenylacetaldehyde
hydrochloride, mp. 182.degree.-184.degree. C.,
[.alpha.].sub.589.sup..degree. =+7.7.degree. (c=20.1 mg/ml, EtOH,
d=10 cm)
Analyis: calculated: C 73.9, H 8.6, Cl 9.5, N 3.8. found: C 73.9, H
8.5, Cl 9.5, N 3.8.
(The optically active starting materials for the synthesis of the
substances 2 and 3 are described in German Laid-Open Application
DOS No. 3,344,755.)
EXAMPLE 4
2-[3-[(Phenylethyl)-methylamino]-propyl]-diphenylacetaldehyde
Analysis: calculated: C 84.1, H 7.9, N 3.8. found: C 83.9, H 7.8, N
3.8.
EXAMPLE 5
2-[3-[(3-Methoxyphenylethyl)-methylamino]-propyl]-2-dodecyl-3-methoxyphenyl
acetaldehyde
Analysis: calculated: C 78.0, H 10.2, N 2.7. found: C 78.0, H 9.8,
N 2.8.
EXAMPLE 6
2-[3-[(3-Methoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4-dimethoxy
phenylacetaldehyde
Analysis calculated: C 73.0, H 8.7, N 3.3. found: C 73.1, H 8.8, N
3.4.
EXAMPLE 7
2-[3-[(3-Methoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3-methoxyphen
ylacetaldehyde
Analysis: calculated: C 75.5, H 8.9, N 3.5. found: C 75.4, H 9.0, N
3.5.
EXAMPLE 8
2-[3-[(3,4-Dimethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4-dimet
hoxyphenylacetaldehyde
A mixture of 29.9 g (0.1 mole) of
.alpha.-isopropyl-.alpha.-(3-chloropropyl)-3,4-dimethoxyphenylacetaldehyde
and 19.5 g (0.1 mole) of N-methyl-3,4-dimethoxyphenylethylamine in
100 ml of acetonitrile was refluxed for 8 hours in the presence of
27.8 g of anhydrous potassium carbonate, while stirring thoroughly.
After cooling, the reaction mixture was poured into water and
extracted with twice 100 ml of ether. The ether was stripped off,
after which the oily residue was purified by column chromatography
(silica gel, eluent: 9:1 methylene chloride/ethanol). The isolated
base was dissolved in 300 ml of hot isopropanol, and a solution of
oxalic acid in isopropanol was added.
36.7 g (67%) of the hydrogen oxalate of melting point
138.degree.-142.degree. C. (decomposition) were isolated.
The following were obtained similarly to Example 8:
EXAMPLE 9
2-[3-[(3-Methoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4,5-trimeth
oxyphenylacetaldehyde hydrogen oxalate: m.p.
118.degree.-120.degree. C.
EXAMPLE 10
2-[3-[3,4-Dimethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4,5-trim
ethoxyphenylacetaldehyde hydrogen oxalate: mp.
143.degree.-145.degree. C.
EXAMPLE 11
2-[3-[(3,5-Dimethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-dimet
hoxyphenylacetaldehyde hydrogen oxalate: mp. 97.degree.-100.degree.
C.
EXAMPLE 12
2-[3-[(3,5-Diethoxyphenylethyl)-methylamino]-propyl]1-2-isopropyl-3,5-dieth
oxyphenylacetaldehyde hydrogen oxalate: mp. 115.degree.-117.degree.
C.
The following can be obtained similarly to Examples 1 and 2:
EXAMPLE 13
2-[3-[(Phenylethyl)-methylamino]-propyl]-2-isopropyl-3,4-dichlorophenylacet
aldehyde.
EXAMPLE 14
2-[3-[(3,4-Dimethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-4-nitroph
enylacetaldehyde.
EXAMPLE 15
2-[3-[(3-Nitrophenylethyl)-methylamino]-propyl]-2-isopropyl-3,4,5-trimethox
yphenylacetaldehyde.
EXAMPLE 16
2-[3-[(3,4-Dimethylphenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-dimeth
oxyphenylacetaldehyde.
EXAMPLE 17
2-[3-[(3,4-Dichlorophenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-dimeth
oxyphenylacetaldehyde.
EXAMPLE 18
2-[3-[(4-Fluorophenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-dimethoxyp
henylacetaldehyde.
EXAMPLE 19
2-[3-[(3,5-Dimethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4-dichl
orophenylacetaldehyde.
EXAMPLE 20
2-[3-[(3,5-Diethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-dimeth
oxyphenylacetaldehyde.
EXAMPLE 21
2-[3-[(4-Chlorophenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-dimethoxyp
henylacetaldehyde.
EXAMPLE 22
2-[3-[(3-Trifluoromethylphenylethyl)-methylamino]-propyl]-isopropyl-3,5-dim
ethoxyphenylacetaldehyde.
EXAMPLE 23
2-[3-[3,4-Dimethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3-trifluor
omethylphenylacetaldehyde.
EXAMPLE 24
2-[3-[(3,5-Diethoxyphenylethyl)-methylamino]-propyl]-2-isopropylphenylaceta
ldehyde.
EXAMPLE 25
2-[3-[(3,4-Diethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4,5-trim
ethoxyphenylacetaldehyde.
EXAMPLE 26
2-[3-[(3,4-Dimethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-4-butylph
enylacetaldehyde.
EXAMPLE 27
2-[3-[(3-t-Butoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3-t-butoxyph
enylacetaldehyde.
EXAMPLE 28
2-[3-[(3,3-Methylenedioxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,5-
dimethoxyphenylacetaldehyde.
EXAMPLE 29
2-[3-[(3,4-Dimethoxyphenylethyl)-methylamino-propyl]-2-n-octyl-3,4,5-trimet
hoxyphenylacetaldehyde.
EXAMPLE 30
2-[3-[(3-Methoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-1,2,3,4-tetra
hydronaphthalene-6-acetaldehyde.
EXAMPLE 31
2-[3-[(Phenylethyl)-methylamino]-propyl]-2-isopropylindanyl-5-acetaldehyde.
EXAMPLE 32
2-[3-[(1,4-Benzodioxanyl-6-ethyl)-methylamino]-propyl]-2-isopropyl-3,4,5-tr
imethoxyphenylacetalde.
EXAMPLE 33
2-[3-[(3,5-Dimethoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4-ethyl
eneioxyphenylacetaldehyde.
EXAMPLE 34
2-[3-[(1,3-Benzodioxanyl-6-ethyl)-methylamino]-propyl]-2-isopropyl-3,4,5-tr
imethoxyphenylacetaldehyde.
EXAMPLE 35
2-[31-[(Phenylpropyl)-methylamino]-propyl]-2-isopropyl-3,4,5-trimethoxyphen
ylacetaldehyde.
EXAMPLE 36
2-[3-[(Phenylethyl)-methylamino]-propyl]-2-cyclohexylphenylacetaldehyde.
EXAMPLE 37
2-[3-[(3-Methoxyphenylethyl)-methylamino]-propyl]-2-isopropyl-3,4,5-trimeth
oxyphenylacetaldehyde.
EXAMPLE 38
2-[4-[(3-Methoxyphenylethyl)-methylamino]-butyl]-2-isopropylphenylacetaldeh
yde.
EXAMPLE A
Tablets having the following composition are pressed in a
conventional manner on a tablet press:
40 mg of the substance of Example 1
120 mg of corn starch
13.5 mg of gelatine
45 mg of lactose
2.25 mg of Aerosil.RTM. (chemically pure silica consisting of
submicroscopic particles)
6.75 mg of potato starch (as a 6% strength paste)
EXAMPLE B
Coated tablets having the following composition are prepared in a
conventional manner:
20 mg of the substance of Example 1
60 mg of core material
60 mg of sugar-coating material
The core material consists of 9 parts of corn starch, 3 parts of
lactose and 1 part of Luviskol.RTM. VA 64 (60:40
vinylpyrrolidone/vinyl acetate copolymer, cf. Pharm. Ind. 1962,
586). The sugar-coating material consists of 5 parts of sucrose, 2
parts of corn starch, 2 parts of calcium carbonate and 1 part of
talc. The coated tablets prepared in this manner are then provided
with a coating which is resistant to gastric juice.
EXAMPLE C
10 g of the substance of Example 1 are dissolved in 5,000 ml of
water with the addition of NaCl, and the solution is brought to pH
6.0 with 0.1N NaOH so that a blood-isotonic solution is formed.
This solution is introduced into ampoules in an amount of 5 ml per
ampoule, and sterilization is then carried out.
* * * * *